Integrating High Resolution Elemental Mapping with Spatial Transcriptomics to Analyze Metal Based Pathttps://apps.era.nih.gov/gmii/manage/view.era?applId=11296190#hways in Tumor Growth and Spread

Summary Over 90% of cancer fatalities are due to tumor recurrence and metastasis, highlighting a critical need for advanced insights into tumor pathogenesis and the tumor microenvironment (TME). Despite significant advances, a gap remains in fully understanding the dynamic interactions within TME, crucial for assessing metastasis risk and informing future treatment strategies. Metal signaling within tumors plays a pivotal role in cellular processes such as energy metabolism, and collagen remodeling, thereby promoting tumor progression and metastasis. However, the complex interplay between metal abundance and form, transport, cell types, and progression-related pathways is not well understood. Traditionally, genes and metals have been studied in isolation, limiting our understanding of their interactive effects. However, recent advancements in high-resolution transcriptomic and elemental profiling techniques now allow for a comprehensive exploration of all genes and all elements within tissues. This integration presents a challenge, as the optimal methods for combining these data types are not yet fully established. Our research aims to address these gaps by integrating cutting-edge spatial transcriptomics with elemental imaging, creating a spatial multimodal approach that enhances the understanding of tumor biology across different cancer types. Our interdisciplinary team, comprising experts in digital pathology, artificial intelligence, spatial transcriptomics, medical oncology, elemental imaging and biochemistry, is uniquely positioned to translate complex spatial molecular data into actionable prognostic markers. Aim 1 of our proposal focuses on integrating high-resolution elemental imaging with spatial transcriptomics to identify metal-gene niches in the tumor microenvironment. This will enable us to map the distribution of elements and genes at a single-cell resolution, utilizing advanced technologies to uncover new prognostic markers based on clusters of metals and genes. Aim 2 uses both hypothesis-driven and advanced data-driven methods to explore how metals influence tumor recurrence and mortality in patients with colon cancer. Our initial elemental analysis will prioritize metals with established significance in cancer research, expanding to other elements which have not been as thoroughly studied in this domain. In performing this integrative analysis, we will identify metal-related biological pathways that correlate with tumor metastasis. Aim 3 will examine the relationship between metals and tumor recurrence and mortality in women with Triple Negative Breast Cancer (TNBC). Aims 2 and 3 will allow us to understand the broader applicability of metal-targeting therapies across different tumor types. Through this research, we aim to develop comprehensive software that identifies crucial nutrient conditions and metabolic pathways within tumors, informing new therapeutic strategies to enhance patient outcomes. This project will not only advance our understanding of tumor biology and develop biomarkers to spatially locate prognostic regions of metal disruption, but will also pave the way for innovative treatments based on the unique metallomic and genetic landscapes of individual cancers. Project Number: 1R37CA299857-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Joshua Levy | Institution: CEDARS-SINAI MEDICAL CENTER, LOS ANGELES, CA | Award Amount: $743,264 | Activity Code: R37 | Study Section: Molecular Cancer Diagnosis and Classification Study Section[MCDC] View on NIH RePORTER: https://reporter.nih.gov/project-details/11296190